tbuckley/cabot-search huggingface dataset:
Gut microbiome composition may be an indicator of preclinical Alzheimer’s disease
Authors: Aura L. Ferreiro, JooHee Choi, Jian Ryou, Erin P. Newcomer, Regina Thompson, Rebecca M. Bollinger, Carla Hall-Moore, I. Malick Ndao, Laurie Sax, Tammie L. S. Benzinger, Susan L. Stark, David M. Holtzman, Anne M. Fagan, Suzanne E. Schindler, Carlos Cruchaga, Omar H. Butt, John C. Morris, Phillip I. Tarr, Beau M. Ances, Gautam Dantas
Journal: Science Translational Medicine (2023)

Alzheimer’s disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.
AB0754 CLUSTER ANALYSIS OF ARTERIES INVOLVED IN TAKAYASU ARTERITIS
Authors: H. Liao, L. Pan
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Takayasu's arteritis (TAK) is a chronic, large-vessel vasculitis that mostly affects young Asian women[1-4]. Vascular inflammation in TAK primarily invades the aorta and its major branches and often leads to arterial stenosis and aneurysms. At present, there is no relevant research report on how to identify the vascular lesions of organs in the early stage and the relationship between the affected vessels. <h3>Objectives</h3> To investigate the correlation of arterial involvement sites in Takayasu arteritis. <h3>Methods</h3> We retrospectively investigated data of 144 TAK patients. The clinical and image data of the patients were analyzed. We performed cluster analysis according to the affected artery. <h3>Results</h3> cluster analysis revealed five clusters of patients. In cluster one was named "abdominal aortic type". It was characterized by the involvement of arteries in the abdominal aorta, renal artery, coeliac trunk, superior mesenteric artery. In cluster two was named "cardio-cerebral arteries type". It was characterized by the involvement of arteries in the intracranial artery, coronary artery. In cluster three was named "thoracic aorta type". It was characterized by the involvement of arteries in the thoracic aorta and pulmonary artery was observed. In cluster four was named "vertebral artery type". It was characterized by the involvement of arteries in the left vertebral artery, right vertebral artery. In cluster five was named "carotid artery type". It was characterized by the involvement of arteries in the right common carotid artery, left common carotid artery, right subclavian artery, left subclavian artery, innominate artery. <h3>Conclusion</h3> Cluster analysis of the involved sites of Takayasu arteritis could be divided into 5 categories. It is abdominal aortic type, cardio-cerebral arteries type, thoracic aorta type, vertebral artery type and carotid artery type. <h3>References</h3> [1]Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 1990;33(8):1129–34. [2]de Souza AW, de Carvalho JF. Diagnostic and classification criteria of Takayasu arteritis. J Autoimmun. 2014;48-49:79–83. [3]Park SJ, Kim HJ, Park H, Hann HJ, Kim KH, Han S, et al. Incidence, prevalence, mortality and causes of death in Takayasu Arteritis in Korea – A nationwide, population-based study. Int J Cardiol. 2017;235:100–4. [4]Stamatis P. Giant cell arteritis versus Takayasu arteritis: an update. Mediterr J Rheumatol. 2020;31(2):174–82. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
Sex and Tumor-Site Differences in the Association of Alcohol Intake With the Risk of Early-Onset Colorectal Cancer
Authors: Eun Hyo Jin, Kyungdo Han, Cheol Min Shin, Dong Ho Lee, Seung Joo Kang, Joo Hyun Lim, Yoon Jin Choi
Journal: Journal of Clinical Oncology (2023)

PURPOSE Given the increasing incidence of early-onset colorectal cancer (CRC; diagnosed before age 50 years) worldwide, it is important to identify modifiable risk factors. We investigated whether alcohol consumption in the young population correlated with an increased early-onset CRC risk that differed by tumor location and sex. PATIENTS AND METHODS We investigated the association between average daily alcohol consumption and the risk of early-onset CRC among 5,666,576 individuals age 20-49 years using data from the Korean National Health Insurance Service (2009-2019). Alcohol consumption levels of nondrinker, light (reference), moderate, and heavy drinker were defined as 0, &lt;10, 10 to &lt;30, and ≥30 g/d for men and 0, &lt;10, 10 to &lt;20, and ≥20 g/d for women, respectively. Multivariate Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) with 95% CIs. RESULTS We identified 8,314 incident early-onset CRC cases during the follow-up period. Moderate and heavy drinkers showed an increased risk of early-onset CRC compared with light drinkers (aHR, 1.09 [95% CI, 1.02 to 1.16] and aHR, 1.20 [95% CI, 1.11 to 1.29], respectively). Subgroup analysis by tumor location showed positive dose-response significance for early-onset distal colon and rectal cancers, but not for proximal colon cancer. The dose-response association between drinking frequency and risk of early-onset CRC was significant, with a 7%, 14%, and 27% increased risk for 1-2, 3-4, and ≥5 d/wk compared with nondrinkers, respectively. CONCLUSION Excessive alcohol consumption increases the risk of CRC onset before age 50 years. Thus, effective interventions are required to discourage alcohol consumption among young people and to tailor CRC screening approaches for high-risk individuals.
Effect of Brachytherapy With External Beam Radiation Therapy Versus Brachytherapy Alone for Intermediate-Risk Prostate Cancer: NRG Oncology RTOG 0232 Randomized Clinical Trial
Authors: Jeff M. Michalski, Kathryn A. Winter, Bradley R. Prestidge, Martin G. Sanda, Mahul Amin, William S. Bice, Hiram A. Gay, Geoffrey S. Ibbott, Juanita M. Crook, Charles N. Catton, Adam Raben, Walter Bosch, David C. Beyer, Steven J. Frank, Michael A. Papagikos, Seth A. Rosenthal, H. Joseph Barthold, Mack Roach, Jennifer Moughan, Howard M. Sandler
Journal: Journal of Clinical Oncology (2023)

PURPOSE To determine whether addition of external beam radiation therapy (EBRT) to brachytherapy (BT) (COMBO) compared with BT alone would improve 5-year freedom from progression (FFP) in intermediate-risk prostate cancer. METHODS Men with prostate cancer stage cT1c-T2bN0M0, Gleason Score (GS) 2-6 and prostate-specific antigen (PSA) 10-20 or GS 7, and PSA &lt; 10 were eligible. The COMBO arm was EBRT (45 Gy in 25 fractions) to prostate and seminal vesicles followed by BT prostate boost (110 Gy if 125-Iodine, 100 Gy if 103-Pd). BT arm was delivered to prostate only (145 Gy if 125-Iodine, 125 Gy if 103-Pd). The primary end point was FFP: PSA failure (American Society for Therapeutic Radiology and Oncology [ASTRO] or Phoenix definitions), local failure, distant failure, or death. RESULTS Five hundred eighty-eight men were randomly assigned; 579 were eligible: 287 and 292 in COMBO and BT arms, respectively. The median age was 67 years; 89.1% had PSA &lt; 10 ng/mL, 89.1% had GS 7, and 66.7% had T1 disease. There were no differences in FFP. The 5-year FFP-ASTRO was 85.6% (95% CI, 81.4 to 89.7) with COMBO compared with 82.7% (95% CI, 78.3 to 87.1) with BT (odds ratio [OR], 0.80; 95% CI, 0.51 to 1.26; Greenwood T P = .18). The 5-year FFP-Phoenix was 88.0% (95% CI, 84.2 to 91.9) with COMBO compared with 85.5% (95% CI, 81.3 to 89.6) with BT (OR, 0.80; 95% CI, 0.49 to 1.30; Greenwood T P = .19). There were no differences in the rates of genitourinary (GU) or GI acute toxicities. The 5-year cumulative incidence for late GU/GI grade 2+ toxicity is 42.8% (95% CI, 37.0 to 48.6) for COMBO compared with 25.8% (95% CI, 20.9 to 31.0) for BT ( P &lt; .0001). The 5-year cumulative incidence for late GU/GI grade 3+ toxicity is 8.2% (95% CI, 5.4 to 11.8) compared with 3.8% (95% CI, 2.0 to 6.5; P = .006). CONCLUSION Compared with BT, COMBO did not improve FFP for prostate cancer but caused greater toxicity. BT alone can be considered as a standard treatment for men with intermediate-risk prostate cancer.
Use of CAPTURE to Identify Individuals Who May or May Not Require Treatment for Chronic Obstructive Pulmonary Disease
Authors: Yun Li, Fuqiang Wen, Qianli Ma, Rongchang Chen, Yongchang Sun, Tiantian Liu, Chenjuan Gu, Shuling Hu, Jie Song, Chris Compton, Jinping Zheng, Nanshan Zhong, Paul Jones
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: The CAPTURE tool (Chronic Obstructive Pulmonary Disease [COPD] Assessment in Primary Care to Identify Undiagnosed Respiratory Disease and Exacerbation Risk) was developed to identify patients with undiagnosed COPD with an FEV1 <60% predicted or risk of exacerbation as treatment criteria. Objectives: To test the ability of CAPTURE to identify patients requiring treatment because of symptoms or risk of exacerbation or hospitalization. Methods: Data were from COMPASS (Clinical, Radiological and Biological Factors Associated with Disease Progression, Phenotypes and Endotypes of COPD in China), a prospective study of COPD, chronic bronchitis without airflow limitation (postbronchodilator FEV1/FVC ratio ≥0.70), and healthy never-smokers. CAPTURE was tested as questions alone and with peak expiratory flow measurement. Sensitivity, specificity, and positive and negative predicted values (PPV and NPV) were calculated for COPD Assessment Test (CAT) scores ⩾10 versus <10, modified Medical Research Council (mMRC) scores ⩾2 versus <2, and at least one moderate exacerbation or hospitalization in the previous year versus none. Measurements and Main Results: Patients with COPD (n = 1,696) had a mean age of 65 ± 7.5 years, and 90% were male, with a postbronchodilator FEV1 of 66.5 ± 20.1% predicted. Control participants (n = 307) had a mean age of 60.2 ± 7.0 years, and 65% were male, with an FEV1/FVC ratio of 0.78 ± 0.04. CAPTURE using peak expiratory flow showed the best combination of sensitivity and specificity. Sensitivity and specificity were 68.5% and 64.0%, respectively, to detect a CAT score ⩾10; 85.6% and 61.0% to detect an mMRC score ⩾2; 63.5% and 55.6% to detect at least one moderate exacerbation; and 70.2% and 59.4% to detect at least one hospitalization. PPVs ranged from 15.6% (moderate exacerbations) to 47.8% (CAT score). NPVs ranged from 80.8% (CAT score) to 95.6% (mMRC score). Conclusions: CAPTURE has good sensitivity to identify patients with COPD who may require treatment because of increased symptoms or risk of exacerbations or hospitalization, including those with an FEV1 >60% predicted. High NPV values show that CAPTURE can also exclude those who may not require treatment. Clinical trial registered with www.clinicaltrials.gov (NCT04853225).
Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia
Authors: Robert Chiesa, Christos Georgiadis, Farhatullah Syed, Hong Zhan, Annie Etuk, Soragia Athina Gkazi, Roland Preece, Giorgio Ottaviano, Toni Braybrook, Jan Chu, Agnieszka Kubat, Stuart Adams, Rebecca Thomas, Kimberly Gilmour, David O’Connor, Ajay Vora, Waseem Qasim
Journal: New England Journal of Medicine (2023)

Cytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another — specifically, cytosine to thymine — without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated.
Reply to Jha: Understanding the Pathophysiological and Clinical Changes in Lung Injury Models
Authors: Serena Brusatori, Carmelo Zinnato, Tommaso Pozzi, Luigi Camporota, John J. Marini, Luciano Gattinoni
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Reply to: Understanding the Pathophysiological and Clinical Changes in Lung Injury Models." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Hereditary Hemorrhagic Telangiectasia with Diffuse Bronchopulmonary Arteriovenous Malformations
Authors: Masayuki Nakajima, Yuko Morishima, Kensaku Mori, Kazufumi Yoshida, Kenya Kuramoto, Masashi Matsuyama, Takumi Kiwamoto, Yosuke Matsuno, Nobuyuki Hizawa
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Hereditary Hemorrhagic Telangiectasia with Diffuse Bronchopulmonary Arteriovenous Malformations." American Journal of Respiratory and Critical Care Medicine, 208(6), pp. 726–727
Case 18-2023: A 19-Year-Old Woman with Dyspnea and Tachypnea
Authors: Cory A. Perugino, Eric M. Isselbacher, Vinit Baliyan, Sebastian H. Unizony, Rex N. Smith
Journal: New England Journal of Medicine (2023)

A 19-year-old woman presented with respiratory failure. Examination was notable for a diastolic heart murmur and multiple bruits. A diagnosis and management decisions were made.
Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity
Authors: Jan-Bernd Funcke, Barbara Moepps, Julian Roos, Julia von Schnurbein, Kenneth Verstraete, Elke Fröhlich-Reiterer, Katja Kohlsdorf, Adriana Nunziata, Stephanie Brandt, Alexandra Tsirigotaki, Ann Dansercoer, Elisabeth Suppan, Basma Haris, Klaus-Michael Debatin, Savvas N. Savvides, I. Sadaf Farooqi, Khalid Hussain, Peter Gierschik, Pamela Fischer-Posovszky, Martin Wabitsch
Journal: New England Journal of Medicine (2023)

Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.).
Varieties of Chronic Subdural Hematoma and Glucocorticoid Treatment
Authors: Ossama Al-Mefty
Journal: New England Journal of Medicine (2023)

The good physician treats the disease; the great physician treats the patient who has the disease. Almost 50 years ago, it was bewildering to me as a young trainee to learn from the late Dr. Leonard Mallis that at his institution of Mount Sinai Hospital in New York, they were treating chronic subdural hematomas conservatively with prednisone or dexamethasone in order to avoid surgical drainage. The results in 100 patients were later reported by Bender and Christoff.1 Since then, I have continued to witness and share the disappointment in the outcomes of this common but elusive disease, particularly in our . . .
Dexamethasone versus Surgery for Chronic Subdural Hematoma
Authors: Ishita P. Miah, Dana C. Holl, Jurre Blaauw, Hester F. Lingsma, Heleen M. den Hertog, Bram Jacobs, Nyika D. Kruyt, Joukje van der Naalt, Suzanne Polinder, Rob J.M. Groen, Kuan H. Kho, Fop van Kooten, Clemens M.F. Dirven, Wilco C. Peul, Korné Jellema, Ruben Dammers, Niels A. van der Gaag
Journal: New England Journal of Medicine (2023)

The role of glucocorticoids without surgical evacuation in the treatment of chronic subdural hematoma is unclear.In this multicenter, open-label, controlled, noninferiority trial, we randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary end point was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary end points included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale.From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively.In a trial that involved patients with chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be noninferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.).
Wild-Type <i>KRAS</i> Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
Authors: Rafael G. Amado, Michael Wolf, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Daniel J. Freeman, Todd Juan, Robert Sikorski, Sid Suggs, Robert Radinsky, Scott D. Patterson, David D. Chang
Journal: Journal of Clinical Oncology (2023)

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.
Discriminative Accuracy of the CAPTURE Tool for Identifying COPD
Authors: Nin-Chieh Hsu, Hung-Bin Tsai, Chia-Hao Hsu
Journal: JAMA (2023)

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SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas
Authors: Ishani Wickramage, Jeffrey VanWye, Klaas Max, John H. Lockhart, Ismet Hortu, Ezinne F. Mong, John Canfield, Hiran M. Lamabadu Warnakulasuriya Patabendige, Ozlem Guzeloglu-Kayisli, Kimiko Inoue, Atsuo Ogura, Charles J. Lockwood, Kemal M. Akat, Thomas Tuschl, Umit A. Kayisli, Hana Totary-Jain
Journal: Cell Host & Microbe (2023)
Regulation of systemic metabolism by tissue-resident immune cell circuits
Authors: Joey H. Li, Matthew R. Hepworth, Timothy E. O’Sullivan
Journal: Immunity (2023)

Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.